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Magnifico et al. Rare Dis Orphan Drugs J 2023;2:16 https://dx.doi.org/10.20517/rdodj.2023.17 Page 7 of 15

(5) Guidelines for informed consent on genomic testing, sample uses (e.g., research studies) and storage
need to be developed and widely shared within the appropriate workforce;

The European initiative EuroGentest was established by the European Commission to promote accurate
and high-quality genetic diagnostics across Europe, and it was integrated as a working group with the
European Society of Human Genetics (ESHG), with whom in 2016 they published the guidelines for
diagnostic applications of Next Generation Sequencing (NGS) for rare genetic diseases, consisting of 38
statements with a particular focus on WES and sequencing on selected genes identifying small germline
variants (Single Nucleotide Variants (SNVs) and insertions/deletions). In 2021, an update of EuroGentest
guidelines for NGS has been published, including five additional statements (a total of 44 statements) by the
Solve-RD, a Horizon2020-funded project, born with the aim of finding a diagnosis for a large number of
[22]
rare diseases (www.solve-rd.eu) .
GS-based NBS pilot projects
The implementation of GS in newborns triggered great interest in the setting of explorative pilot projects to
assess medical, economic, ethical, and social impact in the healthcare system and among the general
population.

The BabySeq project (ClinicalTrials.gov Identifier: NCT02422511) is a randomized trial on newborns with
the aim to assess the impact of genomic sequencing in the newborn period to screen healthy infants for
current and future health risks and provides data about the feasibility, risks, benefits, and costs of the
integration of exome sequencing in the clinical care of newborns. The BabySeq2 Project (ClinicalTrials.gov
Identifier: NCT05161169) is currently in the recruitment phase and aims to expand and improve the results
obtained in the first study. Results reported for the BabySeq project were obtained by the clinical trial on
159 children from the well-baby nursery at Brigham and Women’s Hospital (127 healthy newborns) and
from the neonatal and pediatric intensive care units at Boston Children’s Hospital in Massachusetts General
[28]
Hospital (32 ill newborns) . 1,514 genes [Supplementary List 1] were curated and classified into three
categories (A, B, or C). Category A includes genes with definitive or strong evidence to cause a highly
penetrant childhood-onset disorder; Category B includes genes based on actionability during childhood;
Category C includes genes that did not meet criteria to be returned in the newborn genome sequencing
[6]
report . A table including an example of genes from category A from Ceyhan-Birsoy et al. (2017) has been
[28]
appended [Supplementary Table 1].
After testing, a newborn genomic sequencing report is generated, including information on pathogenic and
likely pathogenic variants, monogenic disease variants, recessive carrier variants for childhood-onset or
actionable conditions, and pharmacogenomic variants. The analysis also contains information on variants
of uncertain/unknown significance (VUS) indications. However, only a randomized group of families
received newborn GS reports and the results obtained from the study were disclosed to the newborn’s
parents during an in-person consultation by a genetic counselor and physician. The reports are available in
both hospitals and online through a GeneInsight Clinic instance .
[14]

In the BabySeq project, WES analysis uncovered the risk of childhood-onset diseases in 15/159 (9,4%) of
newborns, and none of these was expected based on the clinical histories of babies and their parents. Only
parents of 85/159 newborns accepted to receive information on adult-onset actionable conditions, and in 3/
85 cases a risk was identified. 88% of newborns were carriers of recessive disease and 5% were carriers of
pharmacogenomics variants. Among the newborns with carrier-status variants, 8 of 140 (6%) also had VUS
in one of the reported carrier genes. The number of carrier-status variants ranged from one to seven